Project Summary The candidate in this Mentored Quantitative Research Career Development Award (K25) will be supported in training and research as she makes the transition from mathematics to microbiology. This candidate will combine rigorous training in the ?eld of microbiology with her quantitative and mathematical skills in order to gain an in- depth understanding of bacterial virulence factors associated with in?uenza infection. The training and research will be performed in the Department of Infectious Diseases at St. Jude Children's Research Hospital under the mentorship of Dr. Jonathan McCullers (experimental microbiology) and co-mentorships of Dr. Frederick Adler (theoretical population biology, University of Utah) and Dr. Alan Perelson (theoretical virology and immunology, Los Alamos National Laboratory). The candidate's long-term goal is to establish research independence at the interface of experimental and theoretical microbiology. The objective and goal of this research plan is to de- termine the relative contributions of Streptococcus pneumoniae genes to pathogenesis of in?uenza infections through experimental and theoretical methods and tools. The K25 award will support a research and training program that includes intensive coursework, attendance at conferences, meetings and seminars, hands-on train- ing in experimental microbiology, and a research plan that provides detailed quantitative studies to understand the host-pathogen interactions during bacterial infections in in?uenza-infected hosts. The proposed framework integrates targeted experimental studies, inference of population genetics, and rigorous mathematical modeling. The speci?c aims of this proposal are to: (1) perform experimental in vivo studies of in?uenza-S. pneumoniae infections in mice, (2) develop/re?ne mathematical models and computational simulations of the kinetics of viral- bacterial interactions, and (3) analyze data, estimate parameters and test speci?c hypotheses with regard to the in?uenza-S. pneumoniae dynamics. In the experimental studies, we will measure the ?tness, frequency, and pathogenicity of bacterial mutants produced within the contexts of naive infections and in?uenza infections. Using the mathematical models and simulation, the data will be analyzed in order to obtain quantitative information about the kinetic differences of each individual bacterial mutant and of the entire population of mutants. The it- erative combination of experiments, mathematical models, and computational simulations will result in a detailed and quantitative understanding of the viral-bacterial coinfection dynamics. Such an approach is of critical impor- tance to understand the complex interplay of viral-bacterial interactions and for identi?cation of novel targets for vaccine and antimicrobial development expected to be important to combat these pathogens.